TROP2 is epigenetically inactivated and modulates IGF‐1R signalling in lung adenocarcinoma

Jau‐Chen Lin,Yih‐Leong Chang,Yuh‐Shan Jou,Tzu‐Chieh Lin,Jing‐Yi Wu,Pan‐Chyr Yang,Yi‐Ying Wu,Chen‐Tu Wu,Tse‐Ming Hong

doi:10.1002/emmm.201200222

Abstract

Trop-2, a cell surface glycoprotein, contains both extracellular epidermal growth factor-like and thyroglobulin type-1 repeat domains. Low TROP2 expression was observed in lung adenocarcinoma tissues as compared with their normal counterparts. The lack of expression could be due to either the loss of heterozygosity (LOH) or hypermethylation of the CpG island DNA of TROP2 upstream promoter region as confirmed by bisulphite sequencing and methylation-specific (MS) polymerase chain reaction (PCR). 5-Aza-2′-deoxycytidine treatment on lung cancer cell (CL) lines, CL1-5 and A549, reversed the hypermethylation status and elevated both TROP2 mRNA and protein expression levels. Enforced expression of TROP2 in the lung CL line H1299 reduced AKT as well as ERK activation and suppressed cell proliferation and colony formation. Conversely, silencing TROP2 with shRNA transfection in the less efficiently tumour-forming cell line H322M enhanced AKT activation and increased tumour growth. Trop-2 could attenuate IGF-1R signalling-mediated AKT/β-catenin and ERK activation through a direct binding of IGF1. In conclusion, inactivation of TROP2 due to LOH or by DNA methylation may play an important role in lung cancer tumourigenicity through losing its suppressive effect on IGF-1R signalling and tumour growth.

Highlights

IntroductionResearchers successfully developed an effective strategy for treating non-small cell lung cancer (NSCLC) by targeting the protein tyrosine kinases responsible for activating EGFR and IGF-1R signalling (Lee et al, 2007; Shepherd et al, 2005)
Aberrant expression and/or mutation of membrane proteins may lead to persistent activation of cell-survival signalling,(1) Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei, Taiwan (2) Graduate Institute of Clinical Medicine, National Cheng-Kung University, Tainan, Taiwan (3) Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (4) Department of Pathology, National Taiwan University Hospital, National yThese authors contributed to this work.cellular transformation and invasion as seen in various lung tumours
Genetics of TROP2 and its expression in lung adenocarcinoma TROP2 is located at human chromosome 1p32-p31, which showed a high frequency of loss of heterozygosity (LOH) and microsatellite instability (MI) in the region (Fig 1A)

Summary

Introduction

Researchers successfully developed an effective strategy for treating non-small cell lung cancer (NSCLC) by targeting the protein tyrosine kinases responsible for activating EGFR and IGF-1R signalling (Lee et al, 2007; Shepherd et al, 2005). The TROP2 gene encodes a 323-amino acid cell-surface glycoprotein with a conserved phosphatidylinositol 4,5-bisphosphate (PIP2)-binding domain containing one phosphorylation site (S303) (Cubas et al, 2009) as well as extracellular EGF-like and thyroglobulin type-1 repeat domains. These domains may potentially bind ß 2012 EMBO Molecular Medicine

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Conclusion